The present invention relates to carbapenems and in particular to such compounds containing a carboxy substituted phenyl group. This invention further relates to processes for their preparation, to intermediates in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
The compounds of this invention are antibiotics and can be used in the treatment of any disease that is conventionally treated with antibiotics for example in the treatment of bacterial infection in mammals including humans.
Carbapenems were first isolated from fermentation media in 1974 and were found to have broad spectrum antibacterial activity. Since this discovery substantial investigations have been made into new carbapenem derivatives and many hundreds of patents and scientific papers have been published.
The first, and so far the only, carbapenem to be commercially marketed is imipenem (N-formimidoyl thienamycin). This compound has a broad spectrum of antibacterial activity.
The present invention provides compounds with a broad spectrum of antibacterial activity including against both Gram positive and negative, aerobic and anaerobic bacteria. They exhibit good stability to beta-lactamases. In addition representative compounds of this invention exhibit a very favourable duration of action.
The carbapenem derivatives referred to herein are named in accordance with the generally accepted semi-systematic nomenclature: 
Accordingly the present invention provides a compound of the formula (I): 
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein:
R1 is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;
R2 is hydrogen or C1-4alkyl;
R3 is hydrogen or C1-4alkyl;
R4 and R5 are the same or different and are selected from hydrogen, halo, cyano, C1-4alkyl, nitro, hydroxy, carboxy, C1-4alkoxy, C1-4alkoxycarbonyl, aminosulphonyl, C1-4alkylaminosulphonyl, di-C1-4-alkylaminosulphonyl, carbamoyl, C1-4alkylcarbamoyl, di-C1-4 alkylcarbamoyl, trifluoromethyl, sulphonic acid, amino, C1-4alkylamino, di-C1-4alkylamino, C1-4alkanoylamino, C1-4alkanoyl(Nxe2x80x94C1-4alkyl)amino, C1-4alkanesulphonamido and C1-4alkylS(O)nxe2x80x94 wherein n is zero, one or two:
with the proviso that there is no hydroxy or carboxy substituent in a position ortho to the link to xe2x80x94NR3xe2x80x94.
Alkyl when used herein includes straight chain and branched chain substituents for example methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
Preferably R1 is 1-hydroxyethyl.
R2 is hydrogen or C1-4alkyl for example methyl, ethyl, n-propyl, isopropyl or n-butyl. Preferably R2 is hydrogen or methyl and in particular R2 is methyl.
R3 is hydrogen or C1-4alkyl for example methyl, ethyl, n-propyl, isopropyl or n-butyl. Preferably R3 is hydrogen.
R4 and R5 are the same or different and are selected from hydrogen; halo for example fluoro, bromo or chloro; cyano; C1-4alkyl for example methyl, ethyl, n-propyl, isopropyl or n-butyl; nitro; hydroxy; carboxy; C1-4alkoxy for example methoxy or ethoxy; C1-4alkoxycarbonyl for example methoxycarbonyl, ethoxycarbonyl and n-propoxycarbonyl; aminosulphonyl; C1-4alkylaminosulphonyl for example methylaminosulphonyl and ethylaminosulphonyl; di-C1-4alkylaminosulphonyl for example di-methylaminosulphonyl, methylethylaminosulphonyl and di-ethylaminosulphonyl; carbamoyl; C1-4alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl; di-C1-4alkylcarbamoyl for example dimethylcarbamoyl or diethylcarbamoyl; trifluoromethyl; sulphonic acid; amino; C1-4alkylamino for example methylamino or ethylamino; di-C1-4alkylamino for example dimethylamino or diethylamino; C1-4alkanoylamino for example acetamido or propionamido; C1-4alkanoyl(Nxe2x80x94C1-4alkyl)amino for example N-methylacetamido; C1-4alkanesulphonamido for example methanesulphonamido; and C1-4alkylS(O)nxe2x80x94 for example methylthio, methylsulphinyl or methylsulphonyl.
In a particular aspect a suitable class of compounds is that in which R4 and R5 are the same or different and are selected from hydrogen, fluoro, chloro, hydroxy, carboxy, cyano, nitro, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, trifluoromethyl, sulphonic acid, methylsulphinyl, methylsulphonyl, methanesulphonamido or acetamido.
R4 and R5 may both be other than hydrogen but, in general, it is particularly preferred that at least one of R4 and R5 is hydrogen.
Particularly preferred compounds are those in which R4 is hydrogen, carboxy, fluoro, chloro, methyl, methoxy, cyano, sulphonic acid or methoxycarbonyl and R5 is hydrogen.
The present invention covers all epimeric, diastereoisomeric and tautomeric forms of the compounds of the formula (I) wherein the absolute stereochemistry at the 5-position is as illustrated in formula (I). When a bond is represented by a wedge, this indicates that in three dimensions the bond would be coming out of the paper and when a bond is hatched, this indicates that in three dimensions the bond would be going back into the paper. The compounds of the formula (I) have a number of other stereocentres, namely: within the group R1 (when R1 is 1-hydroxyethyl or 1-fluoroethyl); at the 6-position; at the 1-position (when R2 is C1-4alkyl); and at the 2xe2x80x2 and 4xe2x80x2 positions in the pyrrolidine ring: 
Preferred compounds are those in which the beta-lactam ring protons are in trans configuration with respect to one another. When R1 is 1-hydroxyethyl or 1-fluoroethyl it is preferred that the 8-substituent has the R-configuration. Thus a preferred class of compounds is that of the formula (III): 
and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof, wherein R2, R3, R4 and R5 are as hereinbefore defined.
When R2 is C1-4alkyl for example methyl it is preferred that the compound is in the form of the 1R configuration.
Preferred compounds are those in which the pyrrolidine ring has the following absolute stereochemistry at the 2xe2x80x2- and 4xe2x80x2-positions: 
A preferred class of compounds of the present invention is that of the formula (IV): 
and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof wherein R3, R4, and R5 are as defined hereinbefore in formula (I).
Particularly preferred compounds within the formula (IV) are those wherein R3 is hydrogen and R4 and R5 are the same or different and are selected from hydrogen, fluoro, chloro, hydroxy, carboxy, cyano, nitro, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, methanesulphonyl, trifluoromethyl, sulphonic acid, methylsulphinyl, methanesulphonamido or acetamido.
Especially preferred compounds within the formula (IV) are those wherein R3 and R5 are both hydrogen and R4 is hydrogen, carboxy, fluoro, chloro, methyl, methoxy, cyano, sulphonic acid or methoxycarbonyl.
Suitable pharmaceutically acceptable salts include acid addition salts such as hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. For the avoidance of doubt there may be one, two or three salt-forming cations dependent on the number of carboxylic acid functions and the valency of said cations.
Preferred pharmaceutically acceptable salts are sodium and potassium salts. However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically acceptable or not.
In vivo hydrolysable esters are those pharmaceutically acceptable esters that hydrolyse in the human body to produce the parent compound. Such esters can be identified by administering, eg. intravenously to a test animal, the compound under test and subsequently examining the test animal""s body fluids. Suitable in vivo hydrolysable esters for carboxy include C1-6alkoxymethyl esters for example methoxymethyl, C1-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkoxycarbonyloxy-C1-6alkyl esters for example 1-cyclohexyloxycarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C1-6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention. Suitable in vivo hydrolysable ester forming groups for hydroxy include acetyl, propionyl, pivaloyl, C1-4alkoxycarbonyl for example ethoxycarbonyl and phenylacetyl.
Particular compounds of the present invention are:
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-hydroxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-4-chlorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-6-chlorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid, (1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-6-methanesulphonylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-4-fluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-6-fluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-2,4-difluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3,4-dicarboxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-4-hydroxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3,5-dicarboxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(2-carbamoyl-3-carboxyphenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-4-carbamoylphenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-carbamoylphenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-acetamidophenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-4-acetamidophenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-methylsulphonamidophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-sulphophenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-6-carbamoylphenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-2-dimethylaminocarbonylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(5R,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)carbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-4-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-methylphenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-6-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-2-methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-4-methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-6-methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-4,6-dimethoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-methoxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-cyanophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-trifluoromethylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-4,6-difluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-6-methylsulphinylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-methylsulphonylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-fluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-6-cyanophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy Nxe2x80x2-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof.
Preferred compounds of the present invention are:
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-methylphenylcarbamoyl)-pyrrolidin--4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-6-methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-methoxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-cyanophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-6-chlorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid.
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-4-fluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-6-fluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3,4-dicarboxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid.
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3,5-dicarboxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid.
(1R,5S,6S,8R,2xe2x80x2S,4xe2x80x2S)-2-(2-(3-carboxy-5-sulphophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
and pharmaceutically acceptable salts thereof.
In order to use a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for the therapeutic treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, dispersible powders, suppositories and sterile injectable aqueous or oily solutions or suspensions.
The compounds of the present invention may be formulated as dry powder filled vials, which may contain the compound of the present invention alone or as a dry blended mixture. For example an acidic compound of the present invention may be dry blended with an alkali metal carbonate or bicarbonate. Freeze dried formulations of compounds of the present invention, alone or as a mixture with standard excipients, are possible. Standard excipients include structure formers, cryoprotectants and pH modifiers, such as, mannitol, sorbitol, lactose, glucose, sodium chloride, dextran, sucrose, maltose, gelatin, bovine serum albumin (BSA), glycine, mannose, ribose, polyvinylpyrrolidine (PVP), cellulose derivatives, glutamine, inositol, potassium glutamate, erythritol, serine and other amino acids and buffer agents e.g. disodium hydrogen phosphate and potassium citrate.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered with, one or more known drugs selected from other clinically useful antibacterial agents (for example other beta-lactams or aminoglycosides), inhibitors of beta-lactamase (for example clavulanic acid), renal tubular blocking agents (e.g. probenecid) and inhibitors of metabolising enzymes (for example inhibitors of dehydropeptidases, for example Z-2-acylamino-3-substituted propenoates such as cilastatin) and N-acylated amino acids (for example see EP-A-178911) which reduce adverse effects on the kidney.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg and 1 g of the compound of this invention.
A preferred pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection, for example a sterile injectable containing between 1 and 50% w/w of the compound of this invention.
Specific examples of compositions, which are constituted as a 1% solution in water, freeze dried and may be made up by adding 0.9% aqueous sodium chloride solution to give the required concentration, preferably 1 mg-10 mg/ml, are as follows:
Further specific examples of compositions are as above, but where the compound of example 1 is replaced by any one of examples 2 to 37.
The pharmaceutical compositions of the invention will normally be administered to man in order to combat infections caused by bacteria, in the same general manner as that employed for imipenem due allowance being made in terms of dose levels for the potency and duration of action of the compound of the present invention relative to the clinical use of imipenem. Thus each patient will receive a daily intravenous, subcutaneous or intramuscular dose of 0.05 to 5 g, and preferably 0.1 to 2.5 g, of the compound of this invention, the composition being administered 1 to 4 times per day, preferably 1 or 2 times a day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose. Thus a suitable daily oral dose is 0.05 to 5 g of the compound of this invention, the composition being administered 1 to 4 times per day.
In a further aspect the present invention provides a process for preparing the compounds of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof which process comprises deprotecting a compound of the formula (V): 
wherein R2, R4 and R5 are as hereinbefore defined (R4 and R5 being optionally protected if appropriate); xe2x80x94COOR6 and xe2x80x94COOR7 are carboxy or protected carboxy; R8 is a group R3 or an amino protecting group; R9 is hydrogen or an amino protecting group; and R10 is a group R1, protected 1-hydroxyethyl or protected hydroxymethyl; and wherein at least one protecting group is present;
and thereinafter if necessary;
(i) forming a pharmaceutically acceptable salt,
(ii) esterifying to form an in vivo hydrolysable ester.
Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods.
Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
The compounds of the formula (V) are novel and form another aspect of the invention.
Specific examples of protecting groups are given below for the sake of convenience, in which xe2x80x9clowerxe2x80x9d signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
A carboxyl protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
Examples of carboxy protecting groups include straight or branched chain (1-12C)alkyl groups (eg isopropyl, t-butyl); lower alkoxy lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lover alkoxycarbonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (eg trimethylsilylethyl); and (2-6C)alkenyl groups (eg allyl and vinylethyl).
Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis.
Examples of hydroxyl protecting groups include lower alkenyl groups (eg allyl); lower alkanoyl groups (eg acetyl); lower alkoxycarbonyl groups (eg t-butoxycarbonyl); lower alkenyloxycarbonyl groups (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri lower alkylsilyl (eg trimethylsilyl, t-butyldimethylsilyl) and aryl lover alkyl (eg benzyl) groups.
Examples of amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg t-butoxycarbonyl); lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups.
Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as p-nitrobenzyloxycarbonyl, hydrogenation and for groups such as o-nitrobenzyloxycarbonyl, photolytically.
Preferred protecting groups for carboxy and hydroxy groups in compounds of the formula (I) are the groups allyl and p-nitrobenzyl. A preferred method for removal of the allyl group is by palladium catalysis using tetrakis(triphenylphosphine)palladium and Meldrum""s acid, in a dipolar aprotic solvent tetrahydrofuran mixture, such as dimethylsulphoxide/tetrahydrofuran or 1,3-dimethyl-2-oxo-tetrahydropyrimidine/tetrahydrofuran, or an alcohol/tetrahydrofuran mixture such as isopropanol/tetrahydrofuran or ethanol/tetrahydrofuran, preferably at ambient temperature. Alternatively, methylaniline may be used in place of Meldrum""s acid, in dichloromethane. These conditions allow isolation of the product by precipitation of the sodium salt on the addition of a sodium salt such as sodium 2-ethylhexanoate.
A preferred method for removal of the p-nitrobenzyl group is hydrogenation using a palladium catalyst.
In another aspect of the present invention the compounds of the formulae (I) and (V) may be prepared by
a) reacting compounds of the formulae (VI) and (VII): 
wherein R2, R4-R10 are as hereinbefore defined and L is a leaving group, or
b) cyclising a compound of the formula (VIII): 
wherein R2, R4-R10 as hereinbefore defined and R11-R13 are independently selected from C1-6alkoxy, aryloxy, di-C1-6alkylamino and diarylamino or any two of R11-R13 represent o-phenylenedioxy; or one of R11-R13 is C1-4alkyl, allyl, benzyl or phenyl, and the other two values are independently selected from C1-4alkyl, trifluoromethyl or phenyl, wherein any phenyl group is optionally substituted with C1-3alkyl or C1-3alkoxy:
and wherein any functional group is optionally protected and thereinafter if necessary:
(i) removing any protecting groups;
(ii) forming a pharmaceutically acceptable salt;
(iii) esterifying to form an in vivo hydrolysable ester.
Suitably in the compound of the formula (VI) L is the reactive ester of a hydroxy group such as a sulphonate (for example C1-6alkanesulphonyloxy, trifluoromethanesulphonyloxy, benzenesulphonyloxy, toluenesulphonyloxy), a phosphoric ester (for example a diarylphosphoric ester such as diphenylphosphoric ester) or L is a halide (for example chloride). In an alternative L is a sulphoxide for example xe2x80x94SOCHxe2x95x90CHxe2x80x94NHCOCH3 which may be readily displaced. Preferably L is diphenylphosphoric ester (xe2x80x94OP(O)(OPh)2).
Compounds of the formula (VI) and their preparation are well known in the carbapenem literature, for example see EP-A-126587, EP-A-160391, EP-A-243686 and EP-A-343499.
The reaction between the compounds of the formulae (VI) and (VII) is typically performed in the presence of a base such as an organic amine for example di-isopropylethylamine or an inorganic base for example an alkali metal carbonate such as potassium carbonate. The reaction is conveniently performed at a temperature between xe2x88x9225xc2x0 C. and ambient, suitably at about xe2x88x9220xc2x0 C. The reaction is generally performed in an organic solvent such as acetonitrile or dimethylformamide The reaction is generally performed in a manner similar to that described in the literature for similar reactions.
The compounds of the formula (VII) are novel and form another aspect of the present invention.
The compounds of the formula (VII) may be prepared by the deprotection of a compound of the formula (IX): 
wherein R4-R6, R8 and R9 as hereinbefore defined and R14 is a protecting group, for example C1-6alkanoyl, C1-6alkoxycarbonyl or benzoyl. Preferred values for R14 are acetyl and t-butoxycarbonyl. The compounds of the formula (IX) can be converted to the compounds of the formula (VII) by standard methods of deprotection, for example acetyl groups can be removed by basic hydrolysis in aqueous alkanol or alkenol for example allyl alcohol.
The compounds of the formula (IX) are novel and form another aspect of the present invention.
The compounds of the formula (IX) may be prepared by the reaction of an activated derivative of a compound of the formula (X), which may be formed in situ, with a compound of the formula (XI): 
wherein R4-R6, R8, R9 and R14 are as hereinbefore defined. Activated derivatives of the compound of the formula (X) include acid halides, anhydrides and xe2x80x98activatedxe2x80x99 esters such as 1H-benzo[1,2,3] triazol-1-yl, pentafluorophenyl and 2,4,5-trichlorophenyl esters or the benzimidazol-2-yl ester of the thiocarboxylic acid corresponding to (X). The reaction of the compounds of the formulae (X) and (XI) is performed under standard methods, for example in the presence of Vilsmeier reagent (thus forming the reactive derivative of (X) in situ) at temperatures in the region xe2x88x9230xc2x0 C. to 25xc2x0 C., preferably in the region xe2x88x9220xc2x0 C. to 5xc2x0 C.
The compounds of the formulae (X) and (XI) are prepared by standard methods known to the skilled chemist such as the methods of the Examples hereinafter, the methods described in EP-A-126587 or by methods analogous or similar thereto.
Suitably, in the compounds of the formula (VIII), R11-R13 are independently selected from C1-6 alkoxy such as methoxy, ethoxy, isopropoxy, n-propoxy or n-butoxy; aryloxy such as optionally phenoxy; di-C1-6alkylamino such as dimethylamino or diethylamino; diarylamino such as diphenylamino or any two of R11-R13 represent o-phenylenedioxy. Preferably each of R11-R13 have the same value and are C1-6alkoxy for example methoxy, ethoxy, isopropoxy or n-butoxy or are phenoxy.
The compounds of the formula (VIII) are cyclized under conventional conditions known in the art to form compounds of the formula (V). Typical conditions are heating in a substantially inert organic solvent such as toluene, xylene or ethyl acetate at temperatures in the region 60-150xc2x0 C. Typically the reaction is performed in an atmosphere of nitrogen and is carried out in the presence of a radical scavenger for example hydroquinone.
The compounds of the formula (VIII) may be formed and cyclized in situ. The compounds of the formula (VIII) may conveniently be prepared by reacting compounds of the formulae (XII) and (XIII): 
PR11R12R13xe2x80x83xe2x80x83(XIII)
wherein R2, and R4-R13 are as hereinbefore defined. Suitably the compound of the formula (XIII) is a phosphite or is the functional equivalent of such a compound.
The reaction between the compounds of the formulae (XII) and (XIII) is conveniently performed in an organic solvent such as toluene, xylene, ethyl acetate, chloroform, dichloromethane, acetonitrile or dimethylformamide. Typically the reaction is carried out at an elevated temperature for example 60-150xc2x0 C.
The compounds of the formula (XII) may be prepared by a number of methods known in the art. For example the compounds of the formula (XII) may be prepared by the acylation of a compound of the formula (XIV): 
wherein R2, R4-R6, and R8-R10 are as hereinbefore defined with a compound of the formula (XV):
Clxe2x80x94COxe2x80x94COOR7xe2x80x83xe2x80x83(XV)
wherein R7 is as hereinbefore defined.
The compounds of the formula (XIV) may be prepared by reacting compounds of the formulae (XVI) and (VII): 
wherein R2 and R10 are as hereinbefore defined. The compounds of the formula (XVI) are known in the art and may be reacted with the compounds of the formula (VII) under conventional acylation methods known in the art.
Compounds of the formulae (VII), (XII) and (XIV) are novel and, as such, form another aspect of this invention.
The following biological test methods, data and Examples serve to illustrate the present invention.
Antibacterial Activity
The pharmaceutically acceptable carbapenem compounds of the present invention are useful antibacterial agents having a broad spectrum of activity in vitro against standard laboratory microorganisms, both Gram-negative and Gram-positive, which are used to screen for activity against pathogenic bacteria. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system. In particular the carbapenems of the present invention show good stability to beta-lactamases and have a particularly good elimination half life in mammals. In general compounds show significant improvement over imipenem.
The antibacterial properties of the compounds of the invention may also be demonstrated in vivo in conventional tests.
Carbapenem compounds have generally been found to be relatively non-toxic to warm-blooded animals, and this generalisation holds true for the compounds of the present invention. Compounds representative of the present invention were administered to mice at doses in excess of those required to afford protection against bacterial infections, and no overt toxic symptoms or side effects attributable to the administered compounds were noted.
The following results were obtained for representative compounds on a standard in vitro test system using Diagnostic Sensitivity Test. The antibacterial activity is described in terms of the minimum inhibitory concentration (MIC) determined by the agar-dilution technique with an inoculum size of 104 CFU/spot.
In the examples:
(a) NMR spectra were taken at 200 MHz or 400 MHz;
(b) Allyloxy means the propen-1-yloxy group xe2x80x94OCH2CHxe2x95x90CH2;
(c) THF means tetrahydrofuran;
(d) DMF means dimethylformamide;
(e) Meldrum""s acid is 2,2-dimethyl-1,3-dioxane-4,6-dione.
(f) Evaporation of solvents was carried out under reduced pressure;
(g) EtOAc means ethyl acetate;
(h) EEDQ means N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline;
(i) DMSO means dimethyl sulfoxide;
(j) DCCI means dicyclohexylcarbodiimide; and
(k) The peak positions in NMR spectra taken in DMSO-d6 and acetic acid-d4 vary depending on the ratio of DMSO to acetic acid.